The overall objective of this grant proposal is the study of the molecular structure of certain blood clotting proteins and their precursors and to define the molecular mechanisms responsible for their function in coagulation and fibrinolysis. Attention is to be focused primarily on four areas, namely: 1) a detailed analysis of the structural changes which occur when human fibrinogen is converted to fibrin and the sequence of digestion of fibrinogen and/or fibrin by human plasmin; it is alos intended to localize the A alpha-chain crosslink sites; 2) the definition of the amino acid sequence of plasma and platelet fibrin stabilizing factors (FSF), particularly the sequence of the active site region of the two molecules; in addition attention will be given to the conformational changes which these two enzymes undergo during the course of their activation and catalysis of crosslink formation in human fibrin; 3) the biochemical characterization of human factor VIII (antihemophilic factor); it is hoped that these studies will resolve the question about whether human factor VIII is a molecule with two activities, i.e., procoagulant activity and von Willebrand factor activity, or whether it is composed of a large carrier subunit (von Willebrand factor activity) and a small, noncovalently bound subunit (procoagulant activity); and 4) the study of the structure-function relationships of plasminogen, primarily focusing attention on the activation process; once this is completed, the same sort of studies will be performed on plasminogens from higher primates.